PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis. Understanding the mechanisms that drive the development and progression of PDA is the greatest hope to identify novel methods for early detection or intervention. Smoking is a known risk factor for pancreatic cancer and cigarette smokers are two or three times more likely to develop pancreatic cancer than nonsmokers. However, the molecular mechanisms underlying smoking-induced development of pancreatic cancer are largely unknown. This proposal will investigate the contribution of smoking-induced carcinogens to the development of pancreatic cancer. It is our hypothesis that smoking-related carcinogens can lead to the formation of a constitutively-active PKD1 fragment in pancreatic acinar cells. We further hypothesize that this active PKD1 fragment in presence of an oncogenic KRAS mutation accelerates development of pancreatic cancer. To test our hypothesis we will: Determine if smoking-induced carcinogens such as BPDE mediate unregulated activation of PKD1 (Specific Aim 1); determine if an unregulated active PKD fragment can be detected in patient samples of smokers versus nonsmokers. (Specific Aim 2); and determine if the smoking- related carcinogen BPDE generates an unregulated active PKD fragment in mice and if this contributes to development of PDA (Specific Aim 3). A successful completion of our project will not only lead to further understanding of how known risk factors such as smoking can contribute to the initiation of pancreatic cancer, but also provide the rationale for developing methods for early detection and intervention.